Intrinsic excitation-inhibition imbalance in major depressive disorder.
Yao Ge, Lijuan Chen, Yu Shen, Ninghua Li, Bo Liu, Xiaojuan Lv, Yan Bai, Wei Wei, Yaping Wu, Kaixin Li, Mengzhu Wang, Meiyun Wang
Journal of affective disorders June 29, 2026 Peer reviewed DOI: 10.1016/j.jad.2026.122164 via PubMed
Summary
Patients with major depressive disorder (MDD) showed significantly reduced Hurst exponent values, indicating an excitation-inhibition imbalance in the parietal and prefrontal-cingulate cortices. The study analyzed resting-state fMRI data from 254 MDD patients and 451 healthy controls, revealing that alterations in the Hurst exponent are linked to specific neurobiological signatures. Additionally, ketamine treatment increased E/I balance in treatment-resistant depression patients, suggesting potential targets for depression treatment.
Study at a glance
| Sample size | 705 |
|---|---|
| Population | 254 patients with major depressive disorder and 451 healthy controls |
| Key finding | Patients with MDD demonstrated significantly reduced Hurst exponent values, indicating an excitation-inhibition imbalance. |
Abstract
Major depressive disorder (MDD) ranks among the foremost contributors to disability worldwide, yet its neurophysiological mechanisms remain poorly understood. Excitation-inhibition (E/I) imbalance has been implicated in MDD pathophysiology, but cortex-wide E/I ratio and its molecular substrates in MDD remain unknown. Resting-state functional magnetic resonance imaging data from 254 MDD patients and 451 healthy controls (HCs) across six sites were analyzed. The Hurst exponent, a biophysically confirmed proxy of E/I balance, was estimated using a fractionally integrated process framework. Neurobiological decoding analyses were performed to map the transcriptomic and neurochemical signatures of cortical E/I imbalance in MDD. An independent ketamine clinical trial dataset (32 treatment-resistant depression patients and 21 HCs) was used to examine ketamine-induced changes in cortical E/I balance. Patients with MDD demonstrated significantly reduced Hurst exponent values, predominantly encompassing the parietal and prefrontal-cingulate cortices. Transcriptomic analysis identified enrichment for neuronal structural organization, nucleic acid metabolism, and mitochondrial function, with preferential overlap with excitatory and inhibitory neuron-specific gene sets. Neurochemically, Hurst exponent alterations were spatially associated with GABAergic, opioidergic, serotonergic, and synaptic density distributions. Divergent group-by-treatment effects were observed in the anterior cingulate and medial prefrontal cortices, with ketamine-induced increases in TRD patients. These findings highlight that prefrontal-cingulate E/I imbalance, anchored to specific transcriptional and neurochemical substrates, may underlie the pathophysiology of MDD and the antidepressant effects of ketamine. The Hurst exponent offers a promising neuroimaging approach for probing E/I imbalance and identifying potential treatment targets in depression.